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Liposomes, Exosomes, and Virosomes: From Modeling Complex
Membrane Processes to Medical Diagnostics and Drug Delivery
Wednesday Speaker Abstracts
33
Cyclotides, Stable Drug Scaffolds Use Phosphatidylethanolamine Lipids as a Switch to
Internalize Inside Cells
Sonia Troeira Henriques
1
, Yen-Hua Huang
1
, Stephanie Chaousis
1
, Marc-Antoine Sani
2
, Aaron
G. Poth
1
, Frances Separovic
2
, David J. Craik
1
.
1
The University of Queensland, Brisbane, Queensland, Australia,
2
University of Melbourne,
Melbourne, Victoria, Australia.
Cyclotides, a large family of peptides from plants, are exceptionally stable and characterized by a
cyclic structure and three disulfide-bonds arranged in a cystine knot. Recently we have found
that cyclotides can be internalized into human cells at non-toxic concentrations. Their
exceptional stability, bioactivities and cell-penetrating properties make cyclotides exciting
templates in drug design and delivery. Using surface plasmon resonance, nuclear magnetic
resonance spectroscopy, mass spectrometry, confocal microscopy and flow cytometry, we have
shown that the prototypic cyclotide, kalata B1, can enter cells via both endocytosis and by direct
membrane translocation. Both pathways are initiated through binding to the cell membrane by
targeting phosphatidylethanolamine-phospholipids at the cell surface and inducing membrane
curvature. This unusual approach to initiate internalization might be employed to deliver drugs
into cells and, in particular, into cancer cells with a higher proportion of surface-exposed
phosphatidylethanolamine-phospholipids. Our findings highlight the potential of using cyclotides
in the development of stable delivery systems for the manipulation of traditionally ‘undruggable’
targets, such as intracellular protein-protein interactions in cancer pathways.